Sprouting angiogenesis is required for new vessel formation during both development and wound repair (Carmeliet et al., Nature 436:193 (2005); Gerhardt et al., J Cell Biol. 161:1163 (2003)). VEGF mediated phospholipase C gamma (PLCγ) activation is essential for endothelial cell (EC) migration, proliferation and tube formation. This pathway is regarded as the canonical signaling pathway during angiogenesis. Recently, it was found that another essential process for angiogenesis is endothelial cell sprouting by filopodia that sense and respond to VEGF gradients (Gerhardt et al., J Cell Biol. 161:1163 (2003); Ruhrberg et al., Genes Dev. 16:2684 (2002); West et al., Development 132:1855 (2005)). Formation of a vascular plexus requires temporary spatial differentiation of endothelial cells into tip and stalk cells, a behavior that is tightly regulated by VEGF-Notch1-delta like 4 (Dll4) signaling (Artavanis-Tsakonas et al., Science 284:770 (1999); Phng et al., Dev. Cell 16:196 (2009); Lobov et al., Proc. Natl. Acad. Sci. 104:3219 (2007)). Many aspects of the signal pathway have been elucidated. However, the feedback regulation that controls tip and stalk cell behavior has not been described.
The major phenotype of the G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) knock out (KO) mouse is defective pulmonary vascular development (Pang et al., Circulation 1524 (2009)). Endothelial cell (EC) function in response to VEGF was significantly impaired as demonstrated by decreased proliferation, tube formation and activation of VEGF mediated PLCγ activation. Interestingly, other vascular beds of GIT1 KO mice were normal except the retina. As both murine retina and lung vascular development occur postnatally, these results suggest a unique role for GIT1 in postnatal angiogenesis (Hislop et al., Paediatr. Respir. Rev. 6:35 (2005)).
The present invention is directed to overcoming these and other deficiencies in the art.